The invention relates to novel tryptase inhibitors which are used in the pharmaceutical industry for preparing medicaments.
The international applications WO95/32945, WO96/09297, WO98/04537, WO99/12918, WO99/24395, WO99/24407 and WO99/40073 describe low-molecular-weight bivalent compounds for use as tryptase inhibitors.
It has now been found that the compounds of the formula I, which are described in more detail below, have surprising and particularly advantageous properties.
The invention provides compounds of the formula I 
in which
M is a central building block of the formula below
xe2x80x94U1"Brketopenst"Cxe2x89xa1C"Brketclosest"nU2xe2x80x94
n is 1 or 2,
U1 and U2 are identical or different and are methylene [xe2x80x94CH2xe2x80x94], ethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94], trimethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], tetramethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94] or isopropylidene [xe2x80x94C(CH3)2xe2x80x94],
A1 is xe2x80x94Oxe2x80x94B1xe2x80x94A3xe2x80x94, xe2x80x94A5xe2x80x94B1xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
A2 is xe2x80x94Oxe2x80x94B2xe2x80x94A4xe2x80x94, xe2x80x94A6xe2x80x94B2xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
B1 and B2 are identical or different and are 1-4C-alkylene,
K1 is xe2x80x94B3xe2x80x94X1, xe2x80x94B3xe2x80x94Y1 or xe2x80x94B3xe2x80x94Z1xe2x80x94B5xe2x80x94X1,
K2 is xe2x80x94B4xe2x80x94X2, xe2x80x94B4xe2x80x94Y2 or xe2x80x94B4xe2x80x94Z2xe2x80x94B6xe2x80x94X2,
B3 and B4 are identical or different and are a bond or 1-4C-alkylene,
B5 and B6 are identical or different and are a bond or 1-2C-alkylene,
X1 and X2 are identical or different and are amino, aminocarbonyl or amidino,
Y1 and Y2 are imidazol-1-yl,
Z1 and Z2 are identical or different and are 5,2-pyridinylene, 6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene, 3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene,
and where on the direct route between the terminal nitrogen atoms 20 to 35, preferably 24 to 29, bonds have to be present, the salts of these compounds, and the N-oxides of the nitrogen-containing heteroaryls, heteroarylenes and heterocycloalkylenes, and their salts, where all those compounds are excluded in which one or more of the variables B3, B4, B5 or B6 adopts the meaning of a bond and there would consequently be a direct linkage of two heteroatoms.
1-4C-alkylene represents straight-chain or branched 1-4C-alkylene radicals, for example the methylene [xe2x80x94CH2xe2x80x94], ethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94], trimethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], tetramethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], 1,2-dimethylethylene [xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94], 1,1-dimethylethylene [xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94], 2,2-dimethylethylene [xe2x80x94CH2xe2x80x94C(CH3)2xe2x80x94], isopropylidene [xe2x80x94C(CH3)2xe2x80x94] or the 1-methylethylene [xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94] radicals.
By definition, the groups Z1 and Z2 are located between groups B3 and B5 (xe2x80x94B3xe2x80x94Z1xe2x80x94B5xe2x80x94) and B4 and B6 (xe2x80x94B4xe2x80x94Z2xe2x80x94B6xe2x80x94), respectively. Accordingly, in the divalent groupings mentioned by way of example (for example 3,6-indolylene), the first number indicates the point of attachment to the group B3 and B4, respectively, and the second number indicates the point of attachment to the group B5 and B6, respectively.
In the context of this application, the term xe2x80x9cterminal nitrogen atomxe2x80x9d means in each case a nitrogen atom in the groups designated X1, X2, Y1 and Y2.
If the group X1 or X2 contains only one nitrogen atom, this nitrogen atom is the terminal nitrogen atom.
If the group X1 or X2 contains a plurality of nitrogen atoms, the nitrogen atom which is furthest from the atom by means of which the bond to the group B3 (B5) or B4 (B6) is established is the terminal nitrogen atom.
If the group Y1 or Y2 contains only one ring nitrogen atom, this ring nitrogen atom is the terminal nitrogen atom.
If the group Y1 or Y2 contains a plurality of ring nitrogen atoms, the ring nitrogen atom which is furthest from the atom by means of which the bond to the group B3 or B4 is established is the terminal nitrogen atom.
According to the invention, the direct route between the nitrogen atoms which act as terminal nitrogen atoms in the groups defined as X1 (Y1) or X2 (Y2) is considered to be the number of bonds which is obtained by counting the bonds which represent the shortest possible connection between the terminal nitrogen atoms.
The following example is meant to illustrate the determination of the number of bonds on the direct route between two terminal nitrogen atoms: 
Here, the direct route comprises 23 bonds.
Preference is given to those compounds of the formula I whose molecular weight is below 600 g/mol.
Particular preference is given to those compounds of the formula I whose molecular weight is below 500 g/mol.
Suitable salts for compounds of the formula I are all acid addition salts. Particular mention may be made of the pharmaceutically acceptable salts of inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the salts are employed in salt preparationxe2x80x94depending on whether a mono- or polybasic acid is concerned and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically unacceptable salts which can be obtained initially as process products, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention, and also their salts, may contain varying amounts of solvents, for example when they are isolated in crystalline form. The invention therefore also embraces all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
Compounds of the formula I which are to be emphasized are those in which
M is a central building block of the formula below
xe2x80x94U1"Brketopenst"Cxe2x89xa1C"Brketclosest"nU2xe2x80x94
n is 1 or 2,
U1 and U2 are identical or different and are methylene [xe2x80x94CH2xe2x80x94], ethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94], trimethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94], tetramethylene [xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94] or isopropylidene [xe2x80x94C(CH3)2xe2x80x94],
A1 is xe2x80x94Oxe2x80x94B1xe2x80x94A3xe2x80x94, xe2x80x94A5xe2x80x94B1xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
A2 is xe2x80x94Oxe2x80x94B2xe2x80x94A4xe2x80x94, xe2x80x94A6xe2x80x94B2xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
A5 and A6 are identical or different and are xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
B1 and B2 are identical or different and are 1-2C-alkylene,
K1 is xe2x80x94B3xe2x80x94Z1xe2x80x94B5xe2x80x94X1,
K2 is xe2x80x94B4xe2x80x94Z2xe2x80x94B6xe2x80x94X2,
B3 and B4 are identical or different and are a bond or 1-2C-alkylene,
B5 and B6 are identical or different and are a bond or 1-2C-alkylene,
X1 and X2 are identical or different and are amino or amidino,
Z1 and Z2 are identical or different and are 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene,
and where on the direct route between the terminal nitrogen atoms 20 to 35, preferably 24 to 29, bonds have to be present,
and the salts of these compounds.
Compounds of the formula I which are to be particularly emphasized are those in which
M is a central building block of the formula below
xe2x80x94U1"Brketopenst"Cxe2x89xa1C"Brketclosest"nU2xe2x80x94
n is 1 or 2,
U1 and U2 are identical or different and are methylene [xe2x80x94CH2xe2x80x94] or isopropylidene [xe2x80x94C(CH3)2xe2x80x94],
A1 is xe2x80x94Oxe2x80x94B1xe2x80x94A3xe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
A2 is xe2x80x94Oxe2x80x94B2xe2x80x94A4xe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, where
A3 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94 and
A4 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
B1 and B2 are identical and are ethylene,
K1 is xe2x80x94B3xe2x80x94Z1xe2x80x94B5xe2x80x94X1,
K2 is xe2x80x94B4xe2x80x94Z2xe2x80x94B6xe2x80x94X2,
B3 and B4 are identical and are methylene,
B5 and B6 are identical and are methylene,
X1 and X2 are identical and are amino,
Z1 and Z2 are identical or different and are 1,3-phenylene, 1,4-phenylene or 1,4-cyclohexylene,
and the salts of these compounds.
Preferred compounds of the formula I are those in which
M is a central building block of the formula below
xe2x80x94U1"Brketopenst"Cxe2x89xa1C"Brketclosest"nU2xe2x80x94
n is 1 or 2,
U1 and U2 are identical and are methylene [xe2x80x94CH2xe2x80x94],
A1 is xe2x80x94Oxe2x80x94B1xe2x80x94A3xe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
A2 is xe2x80x94Oxe2x80x94B2xe2x80x94A4xe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94, where
A3 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94 and
A4 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
B1 and B2 are identical and are ethylene,
K1 is xe2x80x94B3xe2x80x94Z1xe2x80x94B5xe2x80x94X1,
K2 is xe2x80x94B4xe2x80x94Z2xe2x80x94B6xe2x80x94X2,
B3 and B4 are identical and are methylene,
B5 and B6 are identical and are methylene,
X1 and X2 are identical and are amino,
Z1 and Z2 are identical or different and are 1,3-phenylene or 1,4-phenylene,
and the salts of these compounds.
Especially preferred compounds of the formula I are
1,4-bis-(3-aminomethylbenzylaminocarbonyl-1,2-dioxyethyl)-2-butyne,
1,6-bis-(4-aminomethylbenzylaminocarbonyl-1-oxy)-2,4-hexadiyne and
1,4-bis-(3-aminomethylbenzylaminocarbonyl-1-oxy)-2-butyne,
and the salts of these compounds.
The compounds of the formula I are constructed from a large number of building blocks (M, A1, A2, A3, A4, A5, A6, B1, B2, B3, B4, B5, B6, X1, X2, Y1, Y2, Z1 and Z2). In principle, they can be synthesized starting with any of these building blocks. If the compounds of the formula I are constructed largely symmetrically, it is favorable to start the synthesis with the central building block M, whereas in the case of predominantly asymmetrical compounds of the formula I a synthesis starting with one of the end groups K1 or K2 may be advantageous.
Suitable starting materials for synthesizing the compounds of the formula I according to the invention are, for example, 2-butyne-1,4-diol, 2,4-hexadiyne-1,6-diol, 2,4-dimethyl-3-hexyne-2,5-diol or 2,7-dimethyl-3,5-octadiyne-2,7-diol.
Here, the building blocks are linked using always the same pattern, known per se to the person skilled in the art.
It is known to the person skilled in the art that the compounds of the formula I can either be synthesized building block by building block, or by initially constructing relatively large fragments consisting of several individual building blocks, which can then be joined to give the complete molecule.
Owing to the meanings which the individual building blocks of the compounds of the formula I can assume, ether [xe2x80x94Oxe2x80x94], keto [xe2x80x94C(O)xe2x80x94], amide [xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94], carbamate [xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94], carbamide [xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94] or carbonate [xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94] bridges are present in the compounds of the formula I.
How to prepare such bridges is known per se to the person skilled in the art; suitable methods and starting materials for their preparation are described, for example, in March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Third Edition, 1985, John Wiley and Sons.
Ether bridges can be prepared, for example, by the method of Williamson.
Keto bridges can be introduced, for example, as a component of relatively large building blocks, such as, for example, carboxylic acid derivatives.
There is also a large number of known methods for preparing amide bridges. An example which may be mentioned here is the reaction of acyl chlorides with primary or secondary amines. Furthermore, reference is also made to all the methods which have been developed for peptide chemistry.
Carbamate bridges can be prepared, for example, by reacting chloroformates with amines. The chloroformates for their part can be synthesized from alcohols and phosgene. A further variant for constructing carbamate bridges is the addition of alcohols to isocyanates. Similarly to carbamate bridges, it is possible to prepare carbonate bridges starting from chloroformates, by reaction with alcohols (instead of amines).
Carbamide bridges can be prepared, for example, by reacting isocyanates with amines.
The preparation of compounds of the formula I may be shown in an exemplary manner using the reaction schemes below. Reaction scheme 1 shows the preparation of the exemplary compound 1. Reaction scheme 2 shows the preparation of the exemplary compound 2. Reaction scheme 3 shows the preparation of the exemplary compound 3. Other compounds of the formula I can be prepared analogously, or by using the abovementioned methods known per se to the person skilled in the art. 
It is also possible to convert compounds of the formula I by derivatization into other compounds of the formula I. Thus, for example, compounds of the formula I having a nitrogen-containing heteroaryl, heteroarylene or heterocycloalkylene building block can be converted by oxidation into the corresponding N-oxides.
The N-oxidation is carried out in a manner which is likewise known to the person skilled in the art, for example using hydrogen peroxide in methanol or m-chloroperoxybenzoic acid in dichloromethane at room temperature. Which reaction conditions are required in the particular case for carrying out the process is known to the person skilled in the art owing to his expert knowledge.
It is furthermore known to the person skilled in the art that if there are a number of reactive centers on a starting material or intermediate, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description of the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
The isolation and purification of the substances according to the invention is carried out in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular-weight aliphatic alcohol, such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
The examples below serve to illustrate the invention in more detail without restricting it. Likewise, further compounds of the formula I, whose preparation is not explicitly described, can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques.
In the examples below, the abbreviation RT stands for room temperature, calc. for calculated and MS for mass spectrometry. The compounds mentioned by way of example and their salts are the preferred subject of the invention.